Some pre-surgery notes on Alain Enthoven's helpful second opinion.
Explore the source record for details and available documents.
Cost-Benefit Analysis↗
Biomedical subjects
S B Jones
Publications and source records attributed to S B Jones.
Myocardial beta adrenergic receptor coupling to adenylate cyclase during developing septic shock.
The present review is focused on one potential mechanism that may contribute to cardiac failure during developing septic shock. Evidence that sympathetic stimulation is intense in response to septic insult is presented and is related to possible desensitization of adrenergic mechanisms that mobilize cardiac reserve. Disruption of this signal transduction mechanism may be critical in that viable working myocardium becomes reduced as part of the tissue injury process during septic insult, thus requiring increased performance of remaining myocardial tissue. Evidence in support of adrenergic desensitization in the heart during sepsis is presented and is related to current concepts developed from cell-systems. Experiments examining a septic insult and evidence for down regulation of beta-adrenergic receptors, possible uncoupling of beta-receptors to adenylate cyclase, characteristics of beta-receptor agonist binding, and possible internalization of surface receptors are reviewed and discussed. In general, results suggest that changes in the heart occur during sepsis that are typical of adrenergic desensitization. The limited amount of experimental evidence supporting these interpretations and areas of needed research are highlighted.
Adenylyl Cyclases↗
Desensitization of the alpha-2 adrenergic receptor in HT29 and opossum kidney cell lines.
Preincubation of HT29 cells with an alpha-2 adrenergic agonist resulted in a parallel rightward shift in the subsequent dose-response curve to 5-bromo-6-[2-imidazoline-2-yl-amino] quinoxaline (an alpha-2 adrenergic agonist) in inhibiting vasoactive intestinal peptide-stimulated cyclic AMP production. This rightward shift in the dose-response curve, which was concentration and time dependent, was interpreted as desensitization of the alpha-2 adrenergic receptor-mediated inhibition of cyclic AMP production. The fact that no decrease in efficacy was observed appears to result from a receptor reserve. Agonist preincubation effects on subsequent p-aminoclonidine (an alpha-2 adrenergic partial agonist) inhibition and partial irreversible inactivation of receptors confirmed the presence of an alpha-2 adrenergic receptor reserve in HT29 cells. Desensitization appeared to have a heterologous component since inhibition of vasoactive intestinal peptide-stimulated cyclic AMP production by somatostatin was also attenuated. We also assessed the effect of alpha-2 agonist preincubation on subsequent 5-bromo-6-[2-imidazoline-2-yl-amino] quinoxaline inhibition of parathyroid hormone-stimulated cyclic AMP production in OK cells. As with HT29 cells, agonist preincubation resulted in a concentration- and time-dependent shift in the dose-response curve. In both cell lines, long-term preincubation with an alpha-2 adrenergic agonist resulted in a 40% decrease in subsequent [3H]yohimbine binding, indicating down-regulation of the alpha-2 adrenergic receptor.
Animals↗
The vascular response to adrenergic stimulation in pithed rats following endotoxin.
In vivo and in vitro studies have shown that the vascular response to catecholamine is attenuated during endotoxemia. The mechanism of such attenuation is complex and might involve high catecholamine-induced desensitization of adrenoceptors. The purpose of this study was to assess the vascular response to adrenergic stimulation after endotoxin (ETX) administration in pithed rats. In pithed rats, sympathetic outflow is controlled by stimulation, ETX does not elevate norepinephrine (NE), and there are no compensatory reflexes. Rats were pithed, curarized, and adrenal-demedullated. Preganglionic thoracolumbar nerves were stimulated (3 Hz, 10 V, 0.5 msec) for 1 hr after pithing, at which time the first set of frequency and NE-dose responses were assessed by measuring the peak increase in diastolic blood pressure. Intravenous ETX (1.5 mg/kg or 0.5 mg/kg) or saline was administered immediately after these measurements. A sham group was designed to mimic the falling blood pressure pattern seen in the endotoxin group during 1 hr after ETX was given by gradually decreasing the stimulation frequency. The second set of frequency and NE-dose responses were evaluated 1 hr after ETX, saline, or sham treatment. Plasma NE and epinephrine (EPI) were determined before and 1 hr after ETX (1.5 mg/kg) or saline injection. The results showed that blood pressure response to adrenergic stimulation was markedly attenuated in pithed rats following both high and low doses of ETX compared with the saline and sham groups. Plasma NE was not elevated by ETX insult in pithed rats. We propose that mechanisms other than high-catecholamine-induced adrenergic desensitization or hypotension account for the attenuated adrenergic responsiveness of the vasculature following ETX.
Animals↗
Contribution of platelet activating factor to hemodynamic and sympathetic responses to bacterial endotoxin in conscious rats.
The effect of the platelet activating factor (PAF) antagonist WEB 2086 on blood pressure; heart rate; and plasma glucose, lactate, and catecholamine concentrations were examined following either PAF or endotoxin administration in conscious rats. PAF infusion (50 ng/kg/min for 60 min) resulted in a sustained hypotension, with tachycardia and elevated plasma norepinephrine (NE; 1.8-fold increase), epinephrine (E; 6.7-fold increase), and dopamine (DA; 1.0-fold increase) at 30 min after beginning infusion. Plasma NE, E, and DA became 4.1 (NE)-, 17.4 (E)-, and 3.3 (DA)-fold higher than control at 60 min after beginning infusion. Both the hemodynamic and plasma catecholamine alterations induced with PAF were completely blocked with WEB 2086 pretreatment. Bacterial endotoxin treatment (5 mg/kg, i.v. bolus) produced well-characterized responses of hypotension, tachycardia, hyperglycemia, hyperlactacidemia, and an elevation in plasma catecholamines. Whereas complete blockade of the hypotensive and tachycardic effect of endotoxin was achieved with WEB 2086 at 30 min following endotoxin, the increases in plasma catecholamines and lactate elicited by endotoxin were attenuated but remained significantly higher than control levels. Hyperglycemia following endotoxin was not altered by WEB 2086 treatment. In endotoxic rats pretreated with WEB 2086 there was significant hypotension, tachycardia, and hyperlactacidemia and an elevation in plasma catecholamines at both 60 and 120 min, but all were less severe compared to non-WEB 2086-treated endotoxic animals. The results demonstrate that WEB 2086 completely blocked early endotoxin-induced hypotension and tachycardia but not catecholamine elevation following endotoxin. This work suggests that sympathetic activation following endotoxin may be mediated by factors other than hypotension.
Animals↗
Platelet MAO activity and personality variations in normals.
The authors examined platelet MAO activity and several personality variables in 58 non-clinic-referred healthy adult males. The psychological tests administered consisted of the Minnesota Multiphasic Personality Inventory, the Personality Research Form-E, and the Zuckerman Sensation Seeking Scale. The findings replicated previous findings in the literature.
Adult↗
Hexamethylenetetramine: a review.
The available literature on hexamethylenetetramine (hexamine) was reviewed with emphasis on its toxicology and epidemiology, its thermal decomposition and regulatory concerns related to its uses. Large quantities of hexamine are used in the foundry, tire and rubber, and phenolformaldehyde resins industries and in other diverse applications. Excessive exposure to solid hexamine or its vapor has been reported to cause dermatitis and respiratory allergies. Although hexamine produces a positive Ames test, most animal studies have shown hexamine to be of very low genetic risk even in very high doses. The effectiveness of hexamine as an antibacterial agent has been attributed to its slow hydrolysis to ammonia and formaldehyde. Concerns have developed in industries which use hexamine at high temperatures over emissions of HCN, NH3, CO, CO2, nitrogen oxides, and formaldehyde. The studies reviewed are in general agreement that hexamine thermal decomposition in the temperature range of 300-800 degrees C is characterized by an increase in HCN and a decrease in NH3 emissions with increasing temperature. At temperatures of 200-300 degrees C hexamine decomposition is reported to produce mainly ammonia and formaldehyde.
Air Pollutants, Occupational↗
Coronary autoregulation and metabolism in hypothermic rat and ground squirrel hearts.
An isovolumic Langendorff preparation was used to perfuse rat and ground squirrel (Spermophilus tridecemlineatus) hearts at 37, 27, 17, and 7 degrees C. Perfusion pressure (PP) was randomly increased or decreased (40, 60, 70, 110, 120, or 140 mmHg) from a control PP of 90 mmHg. Coronary flow (CF) was measured immediately after each PP change (initial CF) and after stable flow was observed (final CF). Compared with initial flow, final CF was decreased at high PPs or increased at low PPs (autoregulation) in hearts from both species, but rat hearts did not autoregulate CF or develop left ventricular systolic pressure (LVSP) at 7 degrees C. Squirrel hearts generated LVSP at all temperatures and perfusion pressures. LVSP and initial CF were proportional to PP in both species, but squirrel heart LVSP was independent of PP at 7 degrees C. Myocardial O2 consumption (MVO2) was highly correlated with CF in all hearts at 37 degrees C but not at lower temperatures. Squirrel hearts were more efficient (MVO2 vs. HR X LVSP) than rat hearts at low temperatures but less efficient at 37 degrees C. The intrinsic temperature adaptations displayed by squirrel hearts would support continued myocardial function when body temperature and blood pressure fluctuate throughout the stages of hibernation.
Animals↗
Can multiple choice be managed to constrain health care costs?
Explore the source record for details and available documents.
Choice Behavior↗
Dose- and time-dependent changes in plasma catecholamines in response to endotoxin in conscious rats.
Time- and dose-dependent changes in plasma catecholamines, heart rate, and blood pressure were studied in response to sublethal doses of intravenous (i.v.) bacterial endotoxin in conscious male rats. Hypotension occurred with high endotoxin (1,000 micrograms/kg), whereas hypertension occurred in the low-dose group (10 micrograms/kg). All groups had significant tachycardia, which was dose and time dependent, but heart rate was unchanged for the first 2 hr in the low-dose groups (100 and 10 micrograms/kg). Plasma levels of norepinephrine (NE) and epinephrine (E) increased with both dose and time and there was significant interaction of dose and time effects. NE levels increased maximally at 0.5 hr following the highest dose of endotoxin and remained elevated during the protocol. Plasma E levels were maximal at 0.5 hr in the high-dose group, but then declined while remaining significantly higher than the 10 and 100 micrograms/kg endotoxin-treated groups for the duration of the protocol. Peak E levels in the 100 and 10 micrograms/kg group occurred at 3.0 hr and then decreased at the 6.0 hr time. Significant increases in plasma catecholamines and heart rate with endotoxin in the absence of significant hypotension present the possibility that factors other than blood pressure may be mediating efferent sympathetic outflow in endotoxicosis.
Animals↗
Characterization and possible mechanisms of alpha 2-adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production in HT29 cells.
Preincubation with an alpha 2-adrenergic agonist sensitized subsequent forskolin- and vasoactive intestinal peptide-stimulated cyclic AMP production in HT29 cells, a human colonic adenocarcinoma cell line. Preincubation with somatostatin, another agonist negatively coupled to adenylate cyclase, sensitized forskolin-stimulated cyclic AMP production to a lesser extent. alpha 2-Adrenergic agonist preincubation also resulted in desensitization as indicated by a shift to the right in the dose-response curve of a subsequent challenge by an alpha 2-adrenergic agonist. In an effort to elucidate the mechanism for sensitization, we examined protein kinase C and the Na+/H+ antiporter. Whereas these components had marked effects on forskolin stimulation, there was no effect on sensitization. Changes in the concentration of extra-cellular Ca2+ or Mg2+ had no effect on either forskolin stimulation or sensitization. Pertussis toxin pretreatment caused a time-dependent decrease in sensitization, an attenuation of inhibition of cyclic AMP production, and a decrease in subsequent [32P]ADP-ribosylation by pertussis toxin. The time course for these three events was similar, implicating the inhibitory guanine nucleotide regulatory protein in the mechanism for alpha 2-adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production. In addition, pertussis toxin dramatically decreased forskolin-stimulated cyclic AMP production, although with a different time course. These results suggest that the mechanism of sensitization is via an as yet undefined sequence of biochemical events that includes the inhibitory guanine nucleotide regulatory protein, but does not include inhibition of adenylate cyclase nor activation of the Na+/H+ antiporter.
Adenocarcinoma↗
Sedimentation field flow fractionation of mitochondrial and microsomal membranes from corn roots.
Sedimentation field flow fractionation (sed-FFF) is shown to be a valuable procedure for analysis of a wide variety of subcellular particle preparations. The principles underlying this relatively new separation procedure are described. Separation is based on differences between particles in mass and/or density. As in chromatography, the procedure involves relating on-line or off-line measurements made on the effluent from the separation chamber to the elution (retention) time. In this work effluents were monitored for absorbance at 254, 280, and/or 320 nm; collected fractions were assayed for protein content, total ATPase activity, and/or marker enzyme activities and, when appropriate, were examined by electron microscopy. The ratio of the absorbances at 254 and 320 nm was found to provide a sensitive measure of partial resolution of subcellular particles. Preparations containing all of the subcellular particles of corn roots (exclusive of nuclei, cell walls, and ribosomes), and fractions thereof enriched in mitochondria, microsomes, Golgi membranes, or plasma membranes, were examined by sed-FFF. The subcellular particles appear to remain largely intact. All of the particles observed had a mass less than 2 X 10(11) g/mol. All of the preparations were grossly heterogeneous with respect to effective mass distribution. This is due in part to heterogeneity with respect to the organelle of origin. In microsome preparations, components of low, medium, and high density were present in the unretained peak; the retained region had comparatively more high density particles. Plasma membrane preparations had a very wide effective particle mass distribution. The observations suggest that, in addition to its utility for analytic purposes, sed-FFF is likely to prove useful for micro-preparative fractionation of some subcellular particle preparations. Sed-FFF and density gradient centrifugation can be utilized as complementary methods.
Cell Fractionation↗
Plasma catecholamines during E. coli bacteremia in conscious rats.
Fasted, conscious male rats, prepared with arterial and venous cannulas, were given doses (10(10)-10(11) organisms/kg) of live Escherichia coli bacteria. Heart rate and blood pressure were recorded, and arterial plasma samples were taken preinjection and at 30, 180, and 360 min after bacterial administration. Plasma was analyzed for lactate, glucose, norepinephrine (NE), and epinephrine (E). Rats given E. coli were normotensive but with significant tachycardia (P less than 0.05 vs. saline). Plasma NE and E levels increased severalfold during bacteremia (P less than 0.05 for all comparisons). Rats were euglycemic but had a sixfold increase in lactate 6 h (P less than 0.05) after E. coli treatment. Additional rats were subjected to the same protocol but had been made tolerant to bacterial endotoxin by multiple injections over the course of several days. Endotoxin-tolerant rats were also tolerant to live E. coli administration (P less than 0.05, 24 h survival) and had significantly reduced levels of E and NE at 6 h compared with nontolerant bacteremic rats (P less than 0.05). Increases in heart rate and plasma lactate were not significant in endotoxin-tolerant rats. These results suggest profound sympathetic activation during acute bacteremia with attenuated activation in endotoxin-tolerant rats. Tolerance appears to reduce the afferent stimuli that are presumably activated during the course of bacteremia.
Animals↗
Effects of chronic beta-blockade on beta-receptors and adenylate cyclase activity in the canine heart.
To test the hypothesis that beta-receptors 'up-regulate' during chronic beta-blockade, myocardial beta-receptor density, affinity and functional sensitivity were examined in dogs before and after chronic beta-blockade. Membrane preparations from the left ventricle and right atrium were assayed for beta-receptors in 8 control dogs, and 8 dogs given oral nadolol (4 mg/kg) twice a day for 3 weeks. Beta-receptor density and affinity of membrane fractions were determined using 3H-dihydroalprenolol (0.5-20 nM), and Scatchard analysis. Beta-receptor densities after chronic beta-blockade were 419 +/- 28 (mean +/- SEM) and 436 +/- 47 fmol/mg protein in membranes from the left ventricle and right atrium respectively. These values were not significantly different from the left ventricle (412 +/- 25) or the right atrium (413 +/- 25) in control dogs. Beta-receptor affinities were 5.6 +/- 0.5 nM (left ventricle) and 8.5 +/- 1.1 nM (right atrium) after chronic beta-blockade, and not significantly different from control (6.9 +/- 0.7 nM, ventricle; 11.3 +/- 0.9 nM, atrium). Beta-receptor sensitivity was determined in membrane fractions from the left ventricle by analysis of the dose-response relationship between isoproterenol and the formation of c-AMP (pmol/min/mg protein). The concentration of isoproterenol that resulted in 50% of the maximal response was not significantly altered by chronic beta-blockade. Maximally stimulated adenylate cyclase with Gpp(NH)p or NaF was also unchanged by beta-blockade. These results suggest that in the canine heart, chronic beta-blockade does not lead to 'up-regulation' of beta-receptors nor catecholamine supersensitivity.
Adenylyl Cyclases↗
Myocardial beta adrenergic receptors in E. coli induced septic shock.
Explore the source record for details and available documents.
Animals↗
Simultaneous elevation of plasma insulin and catecholamines during endotoxicosis in the conscious and anesthetized rat.
Plasma levels of glucose, insulin and catecholamines were assessed during the early phase of sub-lethal endotoxicosis in fasted male rats which were either conscious or continuously anesthetized with sodium pentobarbital. Exogenous glucose challenge was administered during endotoxicosis to probe insulin release at a time when plasma catecholamines were elevated. An endogenous hyperglycemia occurred following endotoxin but was moderated by continuous pentobarbital anesthesia. Plasma insulin was elevated in the conscious but not anesthetized rats during endogenous hyperglycemia following endotoxin. Hyperglycemia with exogenous glucose elevated plasma insulin levels in both conscious and anesthetized groups and occurred in the presence of elevated levels of norepinephrine, epinephrine and dopamine. Simultaneous elevation of plasma catecholamine and insulin levels during endotoxicosis suggests that glucose utilization may be promoted at the same time that glucose is mobilized through adrenergic mechanisms. These events may contribute to the rapid depletion of carbohydrate stores leading to the hypoglycemia of the agonal stage of endotoxic shock.
Animals↗
Effect of miconazole on growth and aflatoxin production by Aspergillus parasiticus.
At 5 microM, miconazole prevented the growth of Aspergillus parasiticus Speare in a number of media. Sensitivity to miconazole was increased approximately 10-fold in a medium containing glycerol. At sub-inhibitory concentrations, miconazole stimulated aflatoxin synthesis on media which normally support toxin formation. Miconazole inhibited respiration and altered mitochondrial ultrastructure, suggesting that miconazole inhibits growth and stimulates aflatoxin production by depressing mitochondrial activity.
Aflatoxins↗
Alpha 2-adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production.
Preincubation of HT29 human colonic adenocarcinoma cells with alpha 2-adrenergic agonists resulted in a 10- to 20-fold increase in forskolin-stimulated cyclic AMP production as compared to cells preincubated without agonist. Similar results were obtained using either a [3H]adenine prelabeling assay or a cyclic AMP radioimmunoassay to measure cyclic AMP levels. This phenomenon, which is termed sensitization, is alpha 2-adrenergic receptor-mediated and rapid in onset and reversal. Yohimbine, an alpha 2-adrenergic receptor-selective antagonist, blocked norepinephrine-induced sensitization, whereas prazosin (alpha 1-adrenergic) and sotalol (beta-adrenergic) did not. The time for half-maximal sensitization was 5 min and the half-time for reversal was 10 min. Only a 2-fold sensitization of cyclic AMP production stimulated by vasoactive intestinal peptide was observed, indicating that sensitization is relatively selective for forskolin. Sensitization reflects an increased production of cyclic AMP and not a decreased degradation of cyclic AMP, since incubation with a phosphodiesterase inhibitor and forskolin did not mimic sensitization. Increasing the levels of cyclic AMP during the preincubation (using a phosphodiesterase inhibitor) had no effect on sensitization, indicating that sensitization is not caused by decreased cyclic AMP levels during the preincubation. This rapid and dramatic sensitization of forskolin-stimulated cyclic AMP production is a previously unreported effect that can be added to the growing list of alpha 2-adrenergic responses that are not mediated by a decrease in cyclic AMP.
Adenine↗